Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics

项目摘要 这项申请的题目是《PSD95蛋白质相互作用抑制剂作为新型非阿片类镇痛剂的发现》， 解决了治疗慢性神经性疼痛的更有效药物的迫切需要。痛苦是罪魁祸首 与医疗保健系统的接触比任何其他单一原因都多，但治疗方案 神经性疼痛的疗效有限，并有很高的副作用风险，包括阿片成瘾。这些 这些因素每年为本已紧张的美国医疗保健系统增加5600亿至6350亿美元。 N-甲基-D-天冬氨酸受体的谷氨酸激活介导中枢神经系统 敏感化，这与神经病理性疼痛的发展和维持有关。NMDA介导的 中枢敏化依赖于受体上多蛋白质级联复合体的形成，该复合体由 NMDA受体结合到支架蛋白突触后密度蛋白95(PSD95)，并募集 神经元型一氧化氮合酶(NNOS)。通过将这些蛋白质紧密地结合在一起，多个信号级联 被激活导致神经网络重组(可塑性)和神经细胞死亡。小分子和 破坏这种复合体的细胞穿透肽在临床前动物模型中起到有效的止痛剂作用 比非选择性NMDA受体拮抗剂和一氧化氮合酶抑制剂的副作用更好。我们队，第一名 为了发表一种针对这种复合体的小分子，IC87201在临床前疼痛模型中展示了它的有效性。 一种类似的小分子ZL006在临床前中风模型中也是有效的。我们设计并合成了一种独特的 和一组新颖的IC87201和ZL006类似物，将一个分子推进到IND使能研究后 创伤性应激障碍。在确定了对候选分子的担忧之后，我们系统地重新设计了 它产生了一组新的分子。在发展这些分子之前，需要进一步的资金来改进这些分子 他们转向新的使IND成为可能的研究。重要的是，对候选分子的高级毒理学研究 提示靶向特定副作用的风险较低，并预测具有以下特点的化合物的极佳治疗指数 可接受的活性和类似药物的性质。在SBIR第一阶段/第二阶段快速通道应用程序中，Anagin与 我们的合作者和蓝图神经治疗网络将设计和测试改进药物的分子- 类似的特性，在体外和体外试验中确认靶点参与，证明对临床前疼痛有效 模型，并使用行为模型建立治疗边际。我们将推出一位新的临床候选人 分子通过支持IND的研究。不符合我们设定标准的化合物将不会被推进。在… 这些研究的结论，我们将有一个新的临床候选人彻底讯问和准备 慢性疼痛的临床试验中的测试。本提案中总结的数据有力地表明，我们的方法 将产生有效的止痛药，其治疗指标优于开发中或临床上的其他化合物。 这些化合物可能对许多其他谷氨酸驱动的中枢神经系统疾病有用。

Project Summary This application, “Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics”, addresses the critical need for more effective medications to treat chronic neuropathic pain. Pain is responsible for more encounters with the health care system than any other single cause, yet treatment options for neuropathic pain have limited efficacy and carry a high risk for side effects, including opioid addiction. These factors add an additional $560-635 billion annually to an already strained United States health care system. Glutamate activation of N-methyl-D-aspartate (NMDA) receptors mediates central nervous system (CNS) sensitization, which is implicated in the development and maintenance of neuropathic pain. NMDA-mediated central sensitization depends on formation of a multi-protein cascade complex at the receptor consisting of the NMDA receptor bound to the scaffolding protein, postsynaptic density protein 95 (PSD95), and recruitment of neuronal nitric oxide synthase (nNOS). By bringing these proteins close together, multiple signaling cascades are activated leading to neural network reorganization (plasticity) and neuronal cell death. Small molecules and cell penetrating peptides that disrupt this complex act as effective analgesics in preclinical animal models with better side effect profiles than non-selective NMDA receptor antagonists and NOS inhibitors. Our team, the first to publish a small molecule targeting this complex, IC87201, demonstrated its efficacy in preclinical pain models. A similar small molecule, ZL006, is effective in preclinical stroke models. We designed and synthesized a unique and novel set of IC87201 and ZL006 analogs, advancing one molecule into IND-enabling studies for post- traumatic stress disorder. After identifying concerns with the candidate molecule, we systematically redesigned it resulting in a new set of molecules. Further funding is needed to improve on these molecules prior to advancing them toward new IND-enabling studies. Importantly, advanced toxicology studies with the candidate molecule suggest a low risk of target specific side effects and predict an excellent therapeutic index for compounds with acceptable activity and drug-like properties. In this SBIR Phase I/II fast track application, Anagin, in concert with our collaborators and the Blueprint Neurotherapeutics Network, will design and test molecules for improved drug- like properties, confirm target engagement in in vitro and ex vivo assays, demonstrate efficacy in preclinical pain models and establish a therapeutic margin using behavioral models. We will advance a new clinical candidate molecule through IND-enabling studies. Compounds that do not meet our set criteria will not be advanced. At the conclusion of these studies, we will have a new clinical candidate thoroughly interrogated and poised for testing in clinical trials for chronic pain. Data summarized in this proposal strongly suggests that our approach will yield effective analgesics with better therapeutic indices than other compounds in development or the clinic. These compounds are likely to be useful in many other glutamate-driven CNS diseases.